Mark T. Toyama

Ischaemia-reperfusion mechanisms in acute pancreatitis.

The role of ischaemia in the pathogenesis of acute pancreatitis is unknown. Some experimental studies have shown that ischaemia has little effect on the pancreas, while others have found an association with pancreatic injury. Ischaemia-reperfusion damage has been well documented in other sites such as the intestine, cardiac muscle, and skeletal muscle. However, in the pancreas, injury is usually seen only after complete ischaemia, which is uncommon clinically. Experimental chronic pancreatitis is characterized by low pancreatic blood flow, low interstitial pH, and impaired pancreatic tissue oxygenation, which are all findings consistent with the ischaemia-reperfusion mechanisms. Acute pancreatitis is also associated with a reduction in pancreatic blood flow and evidence of free radical generation, similarly suggesting the possibility of ischaemia-reperfusion injury. Ethanol ingestion, which is commonly associated clinically with both chronic and acute pancreatitis, may itself contribute to an ischaemic-reperfusion injury. We have shown that administration of ethanol to cats decreases pancreatic blood flow and may also directly activate neutrophils. Further investigation is needed to determine whether or not these findings are also associated with an ischaemia-reperfusion injury.

Role of nitric oxide in the relationship of pancreatic blood flow and exocrine secretion in cats

BACKGROUND/AIMS Recent studies have suggested that, in the gastrointestinal tract, nitric oxide is an important mediator of alterations in blood flow and, in some organs, a second messenger involved in secretion. This study examined the role of NO in changes in pancreatic blood flow associated with basal and stimulated pancreatic exocrine secretion. METHODS In anesthetized cats, we determined the effects of the NO synthase inhibitor NG-monomethyl-L-arginine (10 mg/kg) and the NO donor sodium nitroprusside (10 micrograms.kg-1.min-1) on pancreatic secretion and blood flow (hydrogen gas clearance). RESULTS NG-monomethyl-L-arginine had no effect on the increase in blood flow associated with secretin stimulation (271 +/- 52 vs. 290 +/- 50 mL.min-1.100 g-1) but reduced that associated with cholecystokinin stimulation (189 +/- 17 vs. 53 +/- 15 mL.min-1.100 g-1; P < 0.001). In contrast, NG-monomethyl-L-arginine significantly reduced both secretin- and cholecystokinin-stimulated secretion. Sodium nitroprusside had no effect on basal blood flow but significantly increased secretion. CONCLUSIONS NO has a selective role in mediating changes in pancreatic perfusion and secretion. It seems to be important in stimulus-secretion coupling with both secretin and cholecystokinin but is only responsible for the accompanying increase in pancreatic blood flow with cholecystokinin.

Pancreatic interstitial pH in human and feline chronic pancreatitis.

BACKGROUND & AIMS Advanced chronic pancreatitis is associated with a reduction in pancreatic blood flow. To determine the physiological significance of this decrease, pancreatic interstitial pH was measured in a model of obstructive chronic pancreatitis in cats and in patients with chronic pancreatitis. METHODS In cats, pancreatic interstitial pH and blood flow were measured serially under basal conditions and after secretory stimulation as chronic pancreatitis evolved. Basal pancreatic interstitial pH was also measured in patients undergoing an operation for chronic pancreatitis or periampullary cancer (controls). RESULTS In normal cats, pancreatic interstitial pH was 7.41 +/- 0.01 and blood flow was 124 mL.min-1.(100 g pancreas-1). With the evolution of chronic pancreatitis, interstitial pH and blood flow progressively decreased to 7.21 +/- 0.04 (P < 0.007) and 75 +/- 11 (P < 0.007), respectively. From 1 to 2 weeks, secretory stimulation reduced pancreatic interstitial pH and blood flow further, but as secretory function was lost, this effect disappeared. In patients with chronic pancreatitis, the interstitial pH was lower (7.02 +/- 0.06) than in controls (7.25 +/- 0.04; P < 0.05). CONCLUSIONS These observations are consistent with the hypothesis that, in chronic pancreatitis, acidic metabolites associated with pancreatic secretion accumulate within the pancreas, probably because of impaired blood flow.

Endoscopic measurement of pancreatic tissue perfusion in patients with chronic pancreatitis and control patients

BACKGROUND Pancreatic blood flow is diminished in experimental models of acute and chronic pancreatitis. We attempted to develop a safe and reliable technique for its measurement in patients and to examine blood flow in patients with chronic pancreatitis and in control subjects. METHOD Pancreatic blood flow was measured using the hydrogen gas clearance technique and an endoscopically placed platinum ductal electrode. Pancreatic blood flow was measured in 12 patients with chronic pancreatitis diagnosed clinically and radiographically, and in 11 control patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) for non-pancreatic pathology. RESULTS Patients with chronic pancreatitis had a significantly lower pancreatic blood flow compared with control patients (51.5 versus 91.7 mL/min/100 gm, p < 0.01). With secretin stimulation pancreatic blood flow increased in two control patients, whereas this notable rise was not seen in three patients with chronic pancreatitis. CONCLUSIONS Measurement of pancreatic blood flow with an endoscopically placed electrode is relatively safe and simple to perform. The scarring and vascular fibrosis associated histologically with chronic pancreatitis is reflected in lower pancreatic blood flow.

Feline model of chronic obstructive pancreatitis : Effects of acute pancreatic duct decompression on blood flow and interstitial pH

BACKGROUND The mechanism by which duct decompression (DD) relieves pain in patients with chronic pancreatitis (CP) is unknown. CP is associated with increased tissue pressure (IP), low pancreatic microvascular blood flow (PMBF), and interstitial pH (pH(I)). The aims of this study were to examine the effects of acute DD on PMBF, increased IP, and pH(I) in cats with CP. METHODS The main pancreatic duct was partially obstructed. At 6 weeks PMBF (ml/min/100g H2 gas clearance), IP (mmHg needle electrode), and pH(I) (microelectrode) were measured before and after secretin stimulation. The duct was then opened, and the studies were repeated. RESULTS PMBF normally increased with secretin stimulation (118 +/- 20 versus 271 +/- 52, P < 0.05). IP was unaltered, and pH(I) decreased as hydrogen ions produced during bicarbonate secretion were dissipated (7.41 +/- 0.01 versus 7.38 +/- 0.01, P < 0.05). In CP, basal PMBF was lower than normal (51 +/- 6 versus 118 +/- 20, P < 0.05) and decreased with stimulation (51 +/- 3.5 versus 31 +/- 3.5, P < 0.05). Basal pancreatic IP was increased (3.47 +/- 0.7 versus 0.05 +/- 0.3, P < 0.05) and increased further with secretory stimulation (3.47 +/- 0.7 versus 4.41 +/- 0.7, P < 0.05) (a compartment syndrome). The low basal pancreatic pH(I) (7.23 +/- 0.02) did not change with secretin stimulation, since bicarbonate secretion was minimal. DD decreased IP (3.66 +/- 0.5 versus 2.81 +/- 0.5, P < 0.05) and increased PMBF (50 +/- 6 versus 79 +/- 6, P < 0.05) and pH(I) (7.24 +/- 0.02 versus 7.34 +/- 0.02, P < 0.05). The normal increase in PMBF after stimulation was restored (79 +/- 6 versus 218 +/- 54, P < 0.05). pH(I) now increased with stimulation (7.34 +/- 0.002 versus 7.37 +/- 0.002, P < 0.05), perhaps due to the marked hyperaemic response. CONCLUSIONS DD acutely restored basal and stimulated PMBF and IP towards normal. Basal pancreatic pH(I) also improved and reflects the underlying ischaemia.

Effect of ethanol on pancreatic interstitial pH and blood flow in cats with chronic pancreatitis.

OBJECTIVE The objective of this study was to investigate the effects of ethanol on pancreatic blood flow and interstitial pH in chronic pancreatitis. BACKGROUND Ethanol is known to contribute to the development of both acute and chronic pancreatitis. However, it is unclear how ethanol precipitates episodes of acute pancreatic inflammation in the setting of chronic pancreatitis. In a model of chronic pancreatitis in cats, it is known that pancreatic blood flow is abnormally low and decreases further after ethanol ingestion. Because it is possible that this reduction in blood flow might be damaging to the pancreas, we investigated the effects of ethanol on pancreatic interstitial pH, an index of pancreatic ischemia. METHODS In normal cats and cats with obstructive chronic pancreatitis, pancreatic blood flow and interstitial pH were measured using the hydrogen gas clearance technique and pH microelectrode, respectively. RESULTS In normal cats, intragastric, but not intravenous, ethanol reduced both pancreatic blood flow by 62% (p < 0.05) and interstitial pH (7.38 +/- 0.03 to 7.20 +/- 0.03, p < 0.05). In cats with chronic pancreatitis in which basal pancreatic blood flow was already only 60% of normal flow, both intragastric and intravenous ethanol decreased both pancreatic blood flow (intragastric, 40% decrease, p < 0.05; intravenous, 34% decrease, p < 0.05) and interstitial pH (intragastric, 7.24 +/- 0.04 to 7.08 +/- 0.04, p < 0.05; intravenous 7.20 +/- 0.08 to 7.07 +/- 0.07, p < 0.05). CONCLUSIONS This profound decrease in pH, lasting up to 2 hours after ethanol exposure in the chronic pancreatitis animals, suggests the possibility of ischemic cellular damage to the pancreas. These findings may explain the pathogenesis of bouts of acute pancreatic inflammation after ethanol ingestion in the setting of chronic disease.

Intragastric Alcohol Causes Endothelin Release from Feline Pancreas

The mechanism by which alcohol causes pancreaticdamage is still largely unknown. One importantcontributory factor may be the endothelins, potentvasoconstricting endothelialderived peptides. The aim of this study was to examine in vivo endothelinrelease from the pancreatic vascular endothelium afteralcohol ingestion. In anesthetized cats immunoreactiveendothelin was measured in serum after instillation of alcohol into the stomach (20 ml, 40%). Afterintragastric alcohol, a rise in endothelin was seen inpancreatic venous effluent (to a mean of 24.5 ±7.7 pg/ml at 60 min). Control serum from the femoral artery exhibited no rise in endothelin (2.11± 1.2 pg/ml). Pancreatic blood flow wassignificantly decreased in a further group to 93% basalafter intravenous infusion of 0.1 nmol/kg ET-1 and to61% after infusion of 1 nmol/kg ET-1. Portal serum levelsof endothelin were 105 pg/ml and 15 pg/ml, respectively,immediately following bolus infusion and decreased tonormal levels within 120 sec. We conclude that the serum endothelin rise after intragastricethanol may be a major factor behind the drop inpancreatic blood flow.